What are the appropriate methods for analyzing patient-reported outcomes in randomized trials when data are missing?

Subjective health measurements using Patient Reported Outcomes (PRO) are increasingly used in randomized trials, particularly for patient groups comparisons. Two main types of analytical strategies can be used for such data: Classical Test Theory (CTT) and Item Response Theory models (IRT). These two strategies display very similar characteristics when data are complete, but in the common case when data are missing, whether IRT or CTT would be the most appropriate remains unknown and was investigated using simulations. We simulated PRO data such as quality of life data. Missing responses to items were simulated as being completely random, depending on an observable covariate or on an unobserved latent trait. The considered CTT-based methods allowed comparing scores using complete-case analysis, personal mean imputations or multiple-imputations based on a two-way procedure. The IRT-based method was the Wald test on a Rasch model including a group covariate. The IRT-based method and the multiple-imputations-based method for CTT displayed the highest observed power and were the only unbiased method whatever the kind of missing data. Online software and Stata® modules compatibles with the innate mi impute suite are provided for performing such analyses. Traditional procedures (listwise deletion and personal mean imputations) should be avoided, due to inevitable problems of biases and lack of power.

Changes in quality of life after a diagnosis of cancer: a 2-year study comparing breast cancer and melanoma patients.

PURPOSE: Longitudinal studies addressing change in health-related quality of life (HRQoL) following a diagnosis of cancer have mainly focused on a single cancer type, and little is known about the differences in HRQoL over time according to the type of tumor. The current study aims to compare the change in HRQoL over 2 years following breast cancer or melanoma diagnosis and socio-demographic variables associated with HRQoL over time. METHODS: Patients recently diagnosed with breast cancer (n = 215) or melanoma (n = 78) completed surveys within 1 month of diagnosis and 6, 12, and 24 months later. Multilevel modeling analyses were used to compare the evolution over time of HRQoL dimensions, as measured by the EORTC QLQ-C30, in both cancers. Longitudinal effect of socio-demographic variables on HRQoL was also assessed. RESULTS: Consistent with the literature, both cancer patients experienced decreased HRQoL scores following the diagnosis before improving over time. However, our analyses revealed that this rebound effect may occur at diverse times over the course of the illness according to the type of cancer. In addition, HRQoL over time was positively associated with age and negatively related to living with a partner regardless of the type of cancer. CONCLUSIONS: The results of the present study suggest that support in hospital units should be specific and depend on the cancer type.

Exploring the impact of staff absenteeism on patient satisfaction using routine databases in a university hospital.

AIM: To explore the influence of staff absenteeism on patient satisfaction using the indicators available in management reports. BACKGROUND: Among factors explaining patient satisfaction, human resource indicators have been studied widely in terms of burnout or job satisfaction, but there have not been many studies related to absenteeism indicators. METHOD: A multilevel analysis was conducted using two routinely compiled databases from 2010 in the clinical departments of a university hospital (France). The staff database monitored absenteeism for short-term medical reasons (5 days or less), non-medical reasons and absences starting at the weekend. The patient satisfaction database was established at the time of discharge. RESULTS: Patient satisfaction related to relationships with staff was significantly and negatively correlated with nurse absenteeism for non-medical reasons (P < 0.05) and with nurse absenteeism starting at weekends (P < 0.05). Patient satisfaction related to the hospital environment was significantly and negatively correlated with nurse assistant absenteeism for short-term medical reasons (P < 0.05). CONCLUSION: Our findings seem to indicate that patient satisfaction is linked to staff absenteeism and should lead to a better understanding of the impact of human resources on patient satisfaction. IMPLICATIONS FOR NURSING MANAGEMENT: To enhance patient satisfaction, managers need to find a way to reduce staff absenteeism, in order to avoid burnout and to improve the atmosphere in the workplace.

Power analysis on the time effect for the longitudinal Rasch model.

Statistics literature in the social, behavioral, and biomedical sciences typically stress the importance of power analysis. Patient Reported Outcomes (PRO) such as quality of life and other perceived health measures (pain, fatigue, stress,...) are increasingly used as important health outcomes in clinical trials or in epidemiological studies. They cannot be directly observed nor measured as other clinical or biological data and they are often collected through questionnaires with binary or polytomous items. The Rasch model is the well known model in the item response theory (IRT) for binary data. The article proposes an approach to evaluate the statistical power of the time effect for the longitudinal Rasch model with two time points. The performance of this method is compared to the one obtained by simulation study. Finally, the proposed approach is illustrated on one subscale of the SF-36 questionnaire.

Mupirocin/chlorexidine to prevent methicillin-resistant Staphylococcus aureus infections: post hoc analysis of a placebo-controlled, randomized trial using mupirocin/chlorhexidine and polymyxin/tobramycin for the prevention of acquired infections in intubated patients.

PURPOSE: The reduction in acquired infections (AI) due to methicillin-resistant Staphylococcus aureus (MRSA) with the mupirocin/chlorhexidine (M/C) decontamination regimen has not been well studied in intubated patients. We performed post hoc analysis of a prior trial to assess the impact of M/C on MRSA AI and colonization. METHODS: We conducted a multicenter, placebo-controlled, randomized, double-blind study with the primary aim to reduce all-cause AI. The two regimens used [topical polymyxin and tobramycin (P/T), nasal mupirocin with chlorhexidine body wash (M/C), or corresponding placebos for each regimen] were administered according to a 2 × 2 factorial design. Participants were intubated patients in the intensive care units of three French university hospitals. The patients enrolled in the study (n = 515) received either active P/T (n = 130), active M/C (n = 130), both active regimens (n = 129), or placebos only (n = 126) for the period of intubation and an additional 24 h. The incidence and incidence rates (per 1,000 study days) of MRSA AI were assessed. Due to the absence of a statistically significant interaction between the two regimens, analysis was performed at the margins by comparing all patient receiving M/C (n = 259) to all patients not receiving M/C (n = 256), and all patients receiving P/T (n = 259) to all patients not receiving P/T (n = 256). RESULTS: Incidence [odds ratio (OR) 0.39, 95 % confidence interval (CI) (0.16-0.96), P = 0.04] and incidence rates [incidence rate ratio (IRR) 0.41, 95 % CI 0.17-0.97, P = 0.05] of MRSA AI were significantly lower with the use of M/C. We also observed an increase in the incidence (OR 2.50, 95 % CI 1.01-6.15, P = 0.05) and the incidence rate (IRR 2.90, 95 % CI 1.20-8.03, P = 0.03) of MRSA AI with the use of P/T. CONCLUSION: Among our study cohort of intubated patients, the use of M/C significantly reduced MRSA AI.

Pharmacoepidemiological characterisation of zolpidem and zopiclone usage.

PURPOSE: Zolpidem and zopiclone are two widely used non-benzodiazepine hypnotics whose usage seems to be associated to pharmacodependence. However, to our knowledge, there has as yet been no published epidemiological study which has compared their abuse or dependence potential. We used a pharmacoepidemiological approach to identify and characterise zolpidem and zopiclone users in real life situations. METHODS: Regular users of zolpidem or zopiclone were identified in the database of a French regional health insurance organisation. A latent class analysis (LCA) was used to identify different subgroups of users of these two hypnotics. RESULTS: The study cohort comprised 25,168 patients who regularly used zolpidem and 21,860 who regularly used zopiclone. The results of the latent class analysis, which enables subgroups with similar patterns of response to be identified, revealed four clinical subtypes of users of zolpidem: non-problematic users, users with associations with hypnotics/anxiolytics or with associated mental disorders, and problematic users. Only three subgroups were identified for zopiclone, and LCA did not discriminate a special class of problematic users for this drug. CONCLUSION: Our analysis indicates that there is a subclass of zolpidem user suggestive of abuse; this was not the case for zopiclone. This methodology is very interesting because it allows analysis of databases and determination of a specific signature of drugs potentially leading to abuse or dependence.

Ammonia plasma concentration and prolonged infusion of remifentanil in patients with acute kidney injury.

BACKGROUND: Glycine is an excipient of remifentanil and may induce side effects. To investigate glycine and ammonia concentration with the use of remifentanil in Intensive Care Unit patients with acute kidney injury (AKI) defined by a decrease in creatinine clearance above 50%. METHODS: Prospective open-label cohort study in three surgical Intensive Care Units. Thirty-three patients with AKI and requiring sedation for at least 72 hours. Sedation with remifentanil and midazolam or propofol was adapted every six hours according to ATICE. Glycine and ammonia plasma concentrations were measured at H0 (start of infusion) and every 12 hours during a continuous intravenous 72 hours remifentanil infusion, and 24 hours after the end of the infusion. Clinical and biological glycine or ammonia toxicity were evaluated. RESULTS: Fifteen patients required continuous veno-venous hemodiafiltration (CVVHDF). Glycine and ammonia plasma concentrations exceeded the normal value respectively for 11 (33%) and 15 (45%) patients before remifentanil infusion (H0). Accumulation of glycine or ammonia was observed neither for patients with or without CVVHDF. For patients without CVVHDF, the plasma ammonia concentration at the end of remifentanil infusion was significantly correlated with the creatinine clearance at H72 (P=0.03) and with the mean rate of remifentanil infusion (P=0.002). No side effect was reported. CONCLUSION: Remifentanil was not associated with an accumulation of glycine or ammonia in patients with AKI. Plasma ammonia concentration was correlated with the mean rate of remifentanil and creatinine clearance. A 72-hours remifentanil infusion appeared safe for sedation of patients with AKI.

Clinical trial: Radiofrequency energy delivery in proton pump inhibitor-dependent gastro-oesophageal reflux disease patients.

BACKGROUND: Radiofrequency (RF) energy delivery is an endoscopic procedure developed for the treatment of gastro-oesophageal reflux disease. AIM: To compare RF and a proton pump inhibitor strategy (PPI) in PPI-dependent patients by carrying out a prospective, randomized trial. METHODS: Patients with PPI-dependent typical reflux symptoms were randomly allocated to either RF or PPI regimen alone. The primary endpoint, evaluated at 6-month, was defined as the possibility for the patient to stop or to decrease PPI use to <50% of the effective dose required at baseline. RESULTS: In the RF group, 18/20 patients stopped (n = 3) or decreased (n = 15) PPI use as compared to eight of 16 in the PPI group (P = 0.01). None of the control patients could stop PPI. Health-related quality of life scores were not different between groups. No significant change in oesophageal acid exposure (OAE) was noted between baseline and 6-months after RF. No severe complication was reported. CONCLUSIONS: Radiofrequency energy delivery is a safe and effective therapeutic option, allowing reduction in or discontinuation of PPI therapy in patients with PPI-dependent symptoms, without loss of quality of life. However, in a majority of patients, PPI therapy cannot be completely stopped. The efficacy of RF does not seem to be related to a decrease in OAE.

Antireflux surgery for non-erosive and erosive reflux disease in community practice.

BACKGROUND: Antireflux surgery has been mainly evaluated in tertiary referral centres. Data regarding post-operative outcome in non-erosive reflux disease are lacking. AIM: To assess long-term outcome after antireflux surgery performed in a community practice setting. METHODS: We selected consecutively 60 non-erosive reflux disease patients and 61 erosive oesophagitis patients with symptomatic gastro-oesophageal reflux disease. After surgery, each subject answered a validated disease-specific health-related quality of life questionnaire and another questionnaire focusing on symptoms, late morbidity and drug use. RESULTS: After a 43-month median follow-up, an excellent outcome was reported by less than two-thirds of patients. Quality of life scores were lower in the non-erosive reflux disease group, especially in female patients. Non-erosive reflux disease patients reported more daily symptoms and more reflux-related symptoms (P = 0.04). Proton-pump inhibitor use was higher in non-erosive reflux disease patients (P < 0.005). Multivariate analysis identified four independent predictive factors associated with better outcome, namely male gender, abnormal preoperative acid exposure, a long duration of symptoms and surgical expertise. CONCLUSIONS: In community practice, the results of antireflux surgery are inferior to those reported by tertiary centres. Outcome seems poorer in non-erosive reflux disease especially in female patients. Nearly one-third of the non-erosive reflux disease patients continue to take proton-pump inhibitors. These results highlight the need for careful selection of patients before antireflux surgery.

A prospective longitudinal study of BK virus infection in 104 renal transplant recipients.

BK virus (BKV) infection during the first year after renal transplantation was studied prospectively in 104 unselected consecutive patients. Viral DNA in urine (DNAuria) and plasma (DNAemia) samples was detected and quantified by real-time PCR. The noncoding control region (NCCR) of BKV isolates was sequenced. DNAuria and DNAemia occurred in 57% and 29% of patients, respectively. Three groups were defined, uninfected patients (group 1, n=45), patients with DNAuria (group 2, n=29) and patients with positive DNAemia (group 3, n=30). Active infection started within the first 3 months in 80% of patients. Cold ischemia duration over 24 h and the administration of tacrolimus were identified as significant risks factors for DNAuria, whereas it remains more frequently negative in patients receiving cyclosporine A. The risk for positive DNAemia was higher in patients with DNAuria (notably for viral load (VL)>4 log/mL) or treated with tacrolimus. No relationship was found with genetic variability in the NCCR sequence. Our data highlight the high frequency of active BKV infection after renal transplantation. Although high VL was detected in some patients, none developed a BKV nephropathy. A prospective follow-up of the whole population during the first year post renal transplantation is thus not useful to predict BKV disease.

Differential effects of two types of antidepressants, amitriptyline and fluoxetine, on anorectal motility and visceral perception.

BACKGROUND: Although antidepressants are used for functional gastrointestinal disorders, the mechanisms of their effects on gut are incompletely understood. AIM: To assess the effects of two types of antidepressants (tricyclic, serotoninergic) on anorectal motility and visceral perception. METHODS: A placebo-controlled, randomized, double-blind, crossover study was performed in 12 healthy male volunteers who received a single oral dose of amitriptyline (80 mg), fluoxetine (40 mg) or placebo. Drug effects were assessed using phasic isobaric distensions of the rectum with an electronic barostat (11 levels from 1 to 51 mmHg) 4 h after drug intake. Maximal rectal volume and pressure, mean and residual pressures at upper anal canal, mean pressure at lower anal canal, defecation sensation (5-level scale) and visceral perception (visual analogue scale) were recorded at each level of distending pressure. RESULTS: Ten subjects completed the study. Compared with placebo, neither amitriptyline nor fluoxetine modified rectal compliance or visceral perception. Compared with placebo, antidepressants significantly reduced mean and residual pressures at upper anal canal (-18%, P = 0.0019, and -27%, P = 0.0002, respectively, for amitriptyline; -26%, P = 0.0001, and -33%, P = 0.0001, respectively, for fluoxetine) whereas only amitriptyline significantly reduced mean pressure at lower anal canal (-16%, P = 0.0008). CONCLUSION: Both antidepressants similarly relaxed the internal anal sphincter, probably through a non-specific mechanism, without modifying visceral perception. Only amitriptyline relaxed the external anal sphincter.

Non-invasive assessment of hepatic iron stores by MRI.

BACKGROUND: MRI has been proposed for non-invasive detection and quantification of liver iron content, but has not been validated as a reproducible and sensitive method, especially in patients with mild iron overload. We aimed to assess the accuracy of a simple, rapid, and easy to implement MRI procedure to detect and quantify hepatic iron stores. METHODS: Of 191 patients recruited, 17 were excluded and 174 studied, 139 in a study group and 35 in a validation group. All patients underwent both percutaneous liver biopsy with biochemical assessment of hepatic iron concentration (B-HIC) and MRI of the liver with various gradient-recalled-echo (GRE) sequences obtained with a 1.5 T magnet. Correlation between liver to muscle (L/M) signal intensity ratio and liver iron concentration was calculated. An algorithm to calculate magnetic resonance hepatic iron concentration (MR-HIC) was developed with data from the study group and then applied to the validation group. FINDINGS: A highly T2-weighted GRE sequence was most sensitive, with 89% sensitivity and 80% specificity in the validation group, with an L/M ratio below 0.88. This threshold allowed us to detect all clinically relevant liver iron overload greater than 60 micromol/g (normal value <36 micromol/g). With other sequences, an L/M ratio less than 1 was highly specific (>87%) for raised hepatic iron concentration. With respect to B-HIC range analysed (3-375 micromol/g), mean difference and 95% CI between B-HIC and MR-HIC were quite similar for study and validation groups (0.8 micromol/g [-6.3 to 7.9] and -2.1 micromol/g [-12.9 to 8.9], respectively). INTERPRETATION: MRI is a rapid, non-invasive, and cost effective technique that could limit use of liver biopsy to assess liver iron content. Our MR-HIC algorithm is designed to be used on various magnetic resonance machines.

Lack of effficacy of botulinum toxin in chronic anal fissure.

BACKGROUND AND AIM: Hypertonicity of internal anal sphincter plays a major role in the persistence of chronic anal fissure. Botulinum toxin could induce internal anal sphincter relaxation without the adverse effects of surgery (long-term faecal incontinence) or topical nitrates (anal burning, headaches, hypotension). METHODS: We conducted a placebo-controlled, randomised, double-blind study to assess the efficacy of a single injection of botulinum toxin in the internal anal sphincter of patients with chronic anal fissure in six ambulatory care clinics. Eligibility criteria included a mean value of post-defecation anal pain >or= 30 mm on a 100 mm visual analogue scale over the week preceding inclusion. Main endpoint was the proportion of patients with symptomatic improvement during the fourth week after inclusion (post-defecation anal pain below 10 mm). RESULTS: Forty-four patients (22 in each group) were included. At inclusion, there was no significant difference between groups on age, sex ratio, pain duration, post-defecation anal pain, analgesic consumption and stool frequency. Ten (45%) and 11 (50%) patients reported symptomatic improvement on the main endpoint (P=0.76) in placebo and botulinum toxin groups, respectively. Ten patients (five in each group) had healed fissure at week 4 and ten patients (five in each group) required surgical treatment between weeks 4 and 12. Similarly, there was no significant difference between groups on other variables between weeks 4 and 12. CONCLUSIONS: The efficacy of a single injection of botulinum toxin in the internal anal sphincter does not differ from that of a placebo in patients with chronic anal fissure.

Ritonavir-saquinavir dual protease inhibitor compared to ritonavir alone in human immunodeficiency virus-infected patients.

The objective of this study was to evaluate the antiretroviral efficacy and safety of ritonavir (600 mg twice a day [b.i.d.])-saquinavir (400 mg b.i.d.) compared to ritonavir (600 mg b.i.d.) in patients pretreated and receiving continued treatment with two nucleoside analogs. The study was placebo controlled, randomized, and double blind. Inclusion criteria included protease inhibitor naive status and a viral load of >10,000 copies/ml. The main end point was viral load at week 24. Forty-seven patients were included (25 given ritonavir and 22 given ritonavir-saquinavir) and monitored until week 48. At inclusion, 23% had had at least one AIDS-defining event. Previous treatment durations (mean and standard deviation) were 42 +/- 25 and 37 +/- 23 months, viral loads were 4.75 +/- 0.62 and 4.76 +/- 0.50 log(10) copies/ml, and CD4 cell counts were 236 +/- 126 and 234 +/- 125/mm(3) in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, viral loads were 2.81 +/- 1.48 and 2.08 +/- 1.14 log(10) copies/ml (P = 0.04) and CD4 cell counts were 330 +/- 151 and 364 +/- 185/mm(3) (P = 0.49) in the ritonavir and ritonavir-saquinavir groups, respectively. Similar results were observed at week 48. Moreover, at week 48, 40 and 68% (P = 0.05) and 28 and 59% (P = 0.03) of patients achieved viral suppression at below 200 and 50 copies/ml in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, six patients in the ritonavir group but only one in the ritonavir-saquinavir group had key mutations conferring resistance to protease inhibitors. Clinical and biological tolerances were similar in both groups. In nucleoside analog-pretreated patients, ritonavir-saquinavir has higher antiretroviral efficacy than and is as well tolerated as ritonavir alone.

Comparison of the two-sided single triangular test to the double triangular test.

Comparative clinical trials are designed to determine whether a new treatment has either superior or different efficacy than a standard, that is, if theta represents a measure of treatment difference, to test the null hypothesis H(0): theta = 0 against the alternative hypothesis H(1) of either superior (theta > 0, one-sided) or different (theta not equal 0, two-sided with H(1)(+): theta > 0 and H(-)(1): theta < 0) efficacy. The triangular test (TT), a group sequential method, allows for early stopping of such trials. Its one-sided version (single TT) and two-sided version (double TT) were implemented in the first release of PEST software. The third release of PEST proposed a modification of the single TT, allowing rejection of H(0) in favor of H(-)(1) when very early data show strong inferiority of the new treatment as compared with the standard. Thus, our aim was to compare this modified single TT, referred to as a two-sided test in PEST 3, with the double TT and two-sided single-stage design (SSD). The statistical properties of the SSD and double TT were perfectly similar under all hypotheses. The modified single TT was underpowered as compared to the two others (the probability of falsely accepting H(0) strictly under H(-)(1) was 0.65 instead of 0.05), but the average sample number function was lower than the one of the double TT under all H(-)(1) hypotheses (-56% strictly under H(-)(1)). We conclude that the modified single TT offers a two-sided conclusion with many fewer patients than the double TT, but at the expense of a strong decrease in power under H(-)(1).

Compartmentalised inducible nitric-oxide synthase activity in septic shock.

BACKGROUND: Previous experimental studies support a role for inducible nitric-oxide synthase (iNOS) in the pathogenesis of severe sepsis. The aim of the study was to characterise iNOS activity in different tissues in patients with septic shock. METHODS: 13 consecutive patients with septic shock caused by cellulitis were enrolled. Skin, muscle, fat, and artery samples were obtained from normal, inflamed, and putrescent areas to measure iNOS activity, and concentrations of tumour necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta). In two patients, iNOS activity was also assessed in peripheral blood mononuclear cells (PBMC) incubated with microorganisms causing the sepsis, or in macrophages isolated from suppurating peritoneal fluid incubated with IL-1beta. FINDINGS: Compared with normal and inflamed areas, iNOS activity was increased in putrescent areas for muscle (71-fold [95% CI 20-259] vs normal areas, 69-fold [19-246] vs inflamed areas; p<0.01 for each) and for fat (68-fold [23-199] and 49-fold [18-137], respectively; p<0.01), but not for skin. Compared with normal areas, putrescent areas of arteries showed increased iNOS expression (1280-fold [598-3153]; p<0.01). Compared with normal areas, TNFalpha and IL-1beta were increased in putrescent areas of arteries (223-fold and 41-fold, respectively; p<0.01 for each). PBMCs and tissue macrophages expressed iNOS. Plasma nitrite/nitrate concentrations inversely correlated with mean arterial pressure and systemic vascular resistance. INTERPRETATION: In human septic shock we found that iNOS activity is compartmentalised at the very site of infection and parallels expression of TNFalpha and IL-1beta. PBMCs and tissue macrophages can be a cellular source for iNOS.

Comparison of four sequential methods allowing for early stopping of comparative clinical trials.

Phase III trials aim to assess whether a new treatment has superior efficacy than a standard treatment. Sequential methods, such as the sequential probability ratio test (SPRT), the triangular test (TT) and so-called one-parameter boundaries (OPB), now allow early stopping of such trials, both in the case of efficacy (alternative hypothesis; H(1)) and in the case of lack of efficacy (null hypothesis; H(0)). We compared the statistical properties of the SPRT and the TT, and of OPB with Pocock (OPB(Delta=0.5)) and O'Brien and Fleming (OPB(Delta=0)) type boundaries, in the setting of one-sided comparative trials with normal response. We studied the type I error (alpha), power (1-beta), average sample number (ASN) and 90th percentile (P90) of the number of patients required to reach a conclusion using simulations. The four tests were also compared with the corresponding single-stage design (SSD). All sequential tests display alpha and 1-beta close to nominal values and, as compared with SSD, allow important decreases in ASN: for example, -48%, -42%, -40% and -31% under H(0) and H(1) for SPRT, TT, OPB(Delta=0.5) and OPB(Delta=0) respectively. For situations between H(0) and H(1), ASNs of all sequential tests were still smaller than the sample size required by SSD, with the TT displaying the largest decrease (-25%). The P90s of the TT and OPB(Delta=0) under H(0) and H(1) were smaller than the P90s of the SPRT and OPB(Delta=0.5), which were similar to the sample size required by SSD. If all sequential tests display approximately similar features, the TT is the most appealing regarding decreases in sample size, especially for situations between H(0) and H(1).

A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin.

CONTEXT: The hypothalamic-pituitary-adrenal axis is a major determinant of the host response to stress. The relationship between its activation and patient outcome is not known. OBJECTIVE: To evaluate the prognostic value of cortisol levels and a short corticotropin stimulation test in patients with septic shock. DESIGN AND SETTING: Prospective inception cohort study conducted between October 1991 and September 1995 in 2 teaching hospital adult intensive care units in France. PARTICIPANTS: A total of 189 consecutive patients who met clinical criteria for septic shock. INTERVENTION: A short corticotropin stimulation test was performed in all patients by intravenously injecting 0.25 mg of tetracosactrin; blood samples were taken immediately before the test (T0) and 30 (T30) and 60 (T60) minutes afterward. MAIN OUTCOME MEASURES: Twenty-eight-day mortality as a function of variables collected at the onset of septic shock, including cortisol levels before the corticotropin test and the cortisol response to corticotropin (delta max, defined as the difference between T0 and the highest value between T30 and T60). RESULTS: The 28-day mortality was 58% (95% confidence interval [CI], 51%-65%) and median time to death was 17 days (95% CI, 14-27 days). In multivariate analysis, independent predictors of death (P < or = .001 for all) were McCabe score greater than 0, organ system failure score greater than 2, arterial lactate level greater than 2.8 mmol/L, ratio of PaO2 to fraction of inspired oxygen no more than 160 mm Hg, cortisol level at T0 greater than 34 microg/dL and delta max no more than 9 microg/dL. Three groups of patient prognoses were identified: good (cortisol level at T0 < or = 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 26%), intermediate (cortisol level at T0 34 microg/dL and delta max < or = 9 microg/dL or cortisol level at T0 > 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 67%), and poor (cortisol level at T0 > 34 microg/dL and delta max < or = 9 microg/dL; 28-day mortality rate, 82%). CONCLUSION: Our data suggest that a short corticotropin test has a good prognostic value and could be helpful in identifying patients with septic shock at high risk for death.

Safety and efficacy of ritonavir and saquinavir in combination with zidovudine and lamivudine.

BACKGROUND: Ritonavir is a potent inhibitor of cytochrome P4503A4 that strongly increases saquinavir bioavailability. In this study we assessed the safety and antiretroviral efficacy of the combination of these two compounds in patients pretreated and receiving continued treatment with zidovudine and lamivudine who were protease inhibitor naive and who had a CD4 cell counts below 200/mm3. METHODS: In this 48-week pilot study, all patients received 600 mg ritonavir and 400 mg saquinavir twice daily. Administration of zidovudine and lamivudine was continued without a change in previous doses. Viral load, CD4 cell count, and the emergence of resistance to the two protease inhibitors were evaluated repeatedly up to week 48. RESULTS: Sixteen patients were included in the study. Previous nucleoside analog treatment duration was 48+/-22 months (mean +/- SD). Two patients quit taking both protease inhibitors within 2 weeks. The ritonavir dose had to be reduced in 10 other patients because of side effects. Between inclusion and week 48, plasma viremia varied from 4.87+/-0.43 to 3.00+/-1.29 log10 copies/mL and CD4 cell counts ranged from 98+/-61 to 250+/-139/mm3. Ten patients (63%) had viral loads below 200 copies/mL and 7 (44%) had viral loads below 50 copies/mL. A single key mutation that conferred ritonavir resistance I84V and V82A/V developed in two patients. A mutation at codon 54 developed in another patient. These mutations were associated with repeated cessations of antiretroviral treatment. No lipodystrophy was observed. CONCLUSION: Ritonavir and saquinavir in combination are quite well tolerated and induce a high and sustained antiretroviral efficacy. A four-drug combination that includes these two protease inhibitors should be considered as a first line of treatment in patients with low CD4 cell counts.

Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve.

AIMS: To investigate the relationship between adrenal gland function and pressor response to noradrenaline in septic shock. METHODS: Basal cortisol level, noradrenaline--mean arterial pressure dose-response curve and cortisol response to intravenous corticotrophin bolus were obtained in nine patients fulfilling usual criteria for septic shock and in six normal volunteers. In patients with septic shock, dose-response curve to noradrenaline was determined a second time 60 min after a 50 mg intravenous hydrocortisone bolus. RESULTS: As compared with controls, patients with septic shock had increased basal cortisol levels (mean+/-s.d.: 1564+/-818 vs 378+/-104 nmol l(-1) , P=0.002, 95% confidence interval for difference in means: [452, 1920]) and a blunted cortisol response to corticotrophin (403+/-461 vs 1132+/-195 nmol l(-1), P=0.008, [-1163, -2951). Five patients had impaired adrenal function reserve. As compared with controls, septic patients displayed a moderate and non significant decrease in pressor sensitivity to noradrenaline (P=0.112). As compared with patients with adequate adrenal response, patients with impaired adrenal function reserve showed a significant decrease in pressor sensitivity to noradrenaline (P=0.038). In septic patients, hydrocortisone improved pressor response to noradrenaline (P=0.032). This effect was more marked in patients with impaired adrenal function reserve so that, as compared with patients with adequate response, the difference was no longer significant (P=0.123). CONCLUSIONS: In septic shock, impaired adrenal function reserve may partly be accounted for by the depressed pressor sensitivity to noradrenaline. The latter may be substantially improved by physiological doses of hydrocortisone.